Diabetes mellitus is a metabolic disorder disease affecting about 10% of the world population. Beside insulin-dependent and insulin-independent diabetes, there is a third type, classified as insulin-resistance. The changes in drug metabolism by diabetes mellitus has long been known in spontaneously diabetic animals as well as those with chemically-induced diabetes. These effects are related to the diabetes rather than the effect of the drug on the liver. There is meager literature on the effect of insulin-resistance on drug metabolism. Three animal models will be used to simulate insulin-resistance; a high fat-diet; N-methyl acetamide and spontaneous ob/ob Zucker rats. Sprague-Dawley adult male rats will be fed a high fat diet consisting of 10% carbohydrate, 60% fat, and 30% protein. The second model, sprague-Dawley adult male rats will be injected with N-methyl acetamide IV single dose of 6.25 g kg1. All other rats will be fed isocaloric diets of 310 Kilojoules day-1. The rats will be tested for insulin-resistance, by measuring their fasting insulin, glucose, triglycerides concentrations as well as glucose incorporation into isolated adipocytes to confirm their insulin resistance status. Rats that are confirmed to be insulin-resistant will be fitted with silicone rubber/polyethylene cannula implanted in the jugular vein to facilitate collection of blood sampling. A recovery period of one week will follow to allow rats to regain their pre-surgery weight. The normal and the insulin resistant rats will receive a multiple IV bolus of aminophylline at 10 mg kg1 every 12 hr. for 5 days. Blood and urine will be collected for theophylline and its metabolites assay by HPLC. Since the rat has a limited blood volume, and a large blood sample is required for measurements, blood samples will be collected in a low dead-volume 1 cc heparinized syringe, after the plasma has been harvested, RBC's will be suspended to the same volume with a donor plasma, and injected back to the rat. Only the fat-fed group diet will be reversed to Purina Rodent Chow to test whether it is possible to reverse their insulin resistance status, by reversing their diet and its effect on theophylline kinetic parameters.